A Straightforward Approach towards Piperidines via Stille Coupling and Subsequent 1,4-Addition of Amines

Abstract

Substituted 4-piperidones are easily obtained from alkynes via molybdenum-catalyzed regioselective hydrostannation and subsequent Stille-coupling of the vinyl stannanes obtained with a,b-unsaturated acyl chlorides. The resulting divinylketones can undergo a double 1,4-addition of amines giving rise to the required 4-piperidones. The best results are obtained if the Stille couplings and the 1,4-additions are combined in a one-pot procedure.Piperidines are an important class of heterocycles, found widely in nature, for example in the large group of piperidine alkaloids. 1 Probably the most famous representative is the poison of the hemlock Conium maculatum, coniin (1), 2 but many other derivatives are highly interesting from a pharmaceutical point of view as well. Hydroxylated piperidines such as isofagomine (2) 3 and related structures are important glycosidase inhibitors, 4 while piperidones such as 3 inhibit human platelet aggregation ( Figure 1). 5 Figure 1Natural and pharmaceutically interesting piperidine alkaloids Therefore, substituted 4-piperidones are highly interesting scaffolds for the synthesis of drug-like molecules. Besides classical approaches such as Dieckmann condensations, 6 hetero-Diels-Alder reactions 7 and cyclizations via 1,4-addition of amines towards vinylic ketones 8 are suitable for the synthesis of these heterocycles.Our group is interested in transition metal catalyzed hydrostannations and the application of this protocol to natural product and heterocycle synthesis. 9 We found that Mo(CO) 3 (CNt-Bu) 3 (MoBl 3 ) is a highly efficient catalyst for the regioselective hydrostannation of terminal alkynes, 10 giving rise to internal vinyl stannanes. 11 These and similar mixed carbonyl/isonitrile complexes were used previously by Trost et al. for allylic alkylations, 12 and we found that MoBl 3 was superior in the hydrostannation reaction to the generally used palladium complexes, 13 especially with respect to regioselectivity. The internal vinyl stannanes can subsequently be subjected to Stille couplings, which makes this approach interesting from a combinatorial point of view. For example, 4-piperidinones should be accessible in three steps from alkynes via regioselective hydrostannation, Stille coupling with a,bunsaturated acyl halides, and subsequent double 1,4-addition of amines (Scheme 1). Scheme 1 Retrosynthetic analysis of substituted 4-piperidonesTo prove this synthetic protocol, we subjected protected propargyl amines 4 to molybdenum-catalyzed hydrostannations (Scheme 2). Under standard reaction conditions, three equivalents of Bu 3 SnH, as reported previously, furnished vinyl stannane 5 in 70-87%. To improve the yield and obtain more reproducible results, we carefully varied the reaction conditions and found that the best results were obtained if only 1.1 equivalents of Bu 3 SnH were added slowly over a period of six to seven hours via syringe pump at room temperature. Under these conditions, 5 was obtained in 95% yield in very pure form [b-product/ g-(E)-product/g-(Z)-product, 93:...